title: The specific α-neurexin interactor calsyntenin-3 promotes excitatory and inhibitory synapse development.
abstract: Perturbations of cell surface synapse-organizing proteins, particularly α-neurexins, contribute to neurodevelopmental and psychiatric disorders. From an unbiased screen, we identify calsyntenin-3 (alcadein-β) as a synapse-organizing protein unique in binding and recruiting α-neurexins, but not β-neurexins. Calsyntenin-3 is present in many pyramidal neurons throughout cortex and hippocampus but is most highly expressed in interneurons. The transmembrane form of calsyntenin-3 can trigger excitatory and inhibitory presynapse differentiation in contacting axons. However, calsyntenin-3-shed ectodomain, which represents about half the calsyntenin-3 pool in brain, suppresses the ability of multiple α-neurexin partners including neuroligin 2 and LRRTM2 to induce presynapse differentiation. Clstn3⁻/⁻ mice show reductions in excitatory and inhibitory synapse density by confocal and electron microscopy and corresponding deficits in synaptic transmission. These results identify calsyntenin-3 as an α-neurexin-specific binding partner required for normal functional GABAergic and glutamatergic synapse development.
authors.affiliation: Brain Research Centre and Department of Psychiatry, University of British Columbia, Vancouver, BC V6T 2B5, Canada.
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Pettem
authors.forename: Daisaku
authors.initials: D
authors.lastname: Yokomaku
authors.forename: Lin
authors.initials: L
authors.lastname: Luo
authors.forename: Michael W
authors.initials: MW
authors.lastname: Linhoff
authors.forename: Tuhina
authors.initials: T
authors.lastname: Prasad
authors.forename: Steven A
authors.initials: SA
authors.lastname: Connor
authors.forename: Tabrez J
authors.initials: TJ
authors.lastname: Siddiqui
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kawabe
authors.forename: Fang
authors.initials: F
authors.lastname: Chen
authors.forename: Ling
authors.initials: L
authors.lastname: Zhang
authors.forename: Gabby
authors.initials: G
authors.lastname: Rudenko
authors.forename: Yu Tian
authors.initials: YT
authors.lastname: Wang
authors.forename: Nils
authors.initials: N
authors.lastname: Brose
authors.forename: Ann Marie
authors.initials: AM
authors.lastname: Craig
mesh_terms: D000818:Animals; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015816:Cell Adhesion Molecules, Neuronal / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000254:growth & development / Q000473:pathology; D006624:Hippocampus / Q000166:cytology* / Q000254:growth & development / Q000378:metabolism / Q000648:ultrastructure; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D019006:Neural Cell Adhesion Molecules / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D051381:Rats; D011956:Receptors, Cell Surface / Q000378:metabolism; D013569:Synapses / Q000235:genetics / Q000378:metabolism*; D009435:Synaptic Transmission / Q000502:physiology*
chemical_list: C585112:CLSTN3 protein, rat; D002135:Calcium-Binding Proteins; D015816:Cell Adhesion Molecules, Neuronal; C547192:LRRTM2 protein, rat; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D019006:Neural Cell Adhesion Molecules; C547193:Nrxn1 protein, rat; D011956:Receptors, Cell Surface; C098003:neuroligin 2